Role of nitric oxide in the vasodilator effect of recombinant human growth hormone in patients with dilated cardiomyopathy.

OBJECTIVE: Dilated cardiomyopathy is characterized by elevated arterial vascular resistance and impaired nitric oxide (NO)-dependent vasodilation. Insulin-like growth factor-I (IGF-I) has been shown to stimulate endothelial NO-synthase resulting in endothelium-dependent vasodilation. Growth hormone (GH) substitution therapy leads in GH-deficient patients to significant increases of IGF-I which may alter systemic vascular resistance by stimulating NO production. This study was designed to evaluate the effects of treatment with recombinant human growth hormone (GH) on NO production and NO-dependent vascular effects in patients with dilated cardiomyopathy. METHODS: 50 patients with dilated cardiomyopathy were randomly assigned to double-blind treatment with 2 I.U. of GH or placebo for 3 months. Central hemodynamics were determined by Swan-Ganz catheter and cardiac output was obtained by the thermodilution method. Serum GH and IGF-I levels were measured and systemic NO production was determined from urinary nitrate and cyclic GMP excretion rates in 42 patients. RESULTS: GH treatment caused in comparison to the placebo group a significant increase of IGF-I by 91 ng/ml (P = 0.0001). Urinary excretion rates of nitrate and cyclic GMP increased also significantly by 38 mumol/mmol creatinine (P = 0.027) and 65 nmol/mmol creatinine (P = 0.003), respectively. The parallel increase of both marker molecules indicates increased systemic NO production during GH treatment. CONCLUSION: GH treatment induces a significant, but moderate increase of systemic NO production in patients with dilated cardiomyopathy. This effect may be mediated by IGF-I stimulating endothelial NO synthase.

Interactions between the renin-angiotensin system and the parasympathetic nervous system in heart failure.

The increase of sympathetic activity in heart failure is accompanied by reduced parasympathetic tone. The renin-angiotensin system (RAS) is often activated in heart failure. It not only has multiple interactions with the sympathetic nervous system but also may influence vagal tone directly via angiotensin II. Animal studies show a reduction of parasympathetic tone by a direct action of angiotensin II in the area postrema, where the blood-brain barrier is absent. It is possible that in addition to the sympathetic and renin-angiotensin systems the parasympathetic nervous system may also influence prognosis in heart failure. Therefore, baroreflex sensitivity (BS) as an index of vagal tone was examined in 35 patients with moderate-to-severe heart failure (NYHA II-III). Independent of the severity of heart failure, BS was lower the higher the plasma renin activity. At 56 months after initial examination, a comparison of the surviving patients (group 1, n = 20) with the patients who died or underwent heart transplantation (group 2, n = 15) did not reveal significant differences in the initial hemodynamic data. However, group 2 patients showed a tendency to higher initial plasma renin activity and a significantly lower BS (1.3 +/- 0.2 versus 2.2 +/- 0.3 ms/mm Hg; p < 0.05). It is concluded that in patients with heart failure a relation between the RAS and the parasympathetic nervous system is likely, as there is a significant negative relationship between BS and plasma renin activity. Among patients with similar degrees of heart failure, low vagal tone identifies patients with a poor prognosis.

[Interaction between the renin system and parasympathetic nervous system in heart failure]. / Beziehung zwischen Reninsystem und parasympathischem Nervensystem bei Herzinsuffizienz.

UNLABELLED: The increase of sympathetic activity in heart failure is accompanied by a reduced parasympathetic tone. The renin-angiotensin system has not only multiple interactions with the sympathetic nervous system, but may also influence vagal tone directly by angiotensin II. Animal studies show a reduction of parasympathetic tone by a direct action of angiotensin II in the area postrema where the blood brain barrier is absent. It is possible that, in addition to the sympathetic and renin-angiotensin system, the parasympathetic nervous system may also influence prognosis in heart failure. Therefore, baroreflex sensitivity as (CBS) an index of vagal tone was examined in 35 patients with moderate to severe heart failure (NYHA II-III). Independent of the severity of heart failure BS was the lower the higher plasma-renin-activity was. Fifty-six months after the initial examination a comparison of the surviving patients (Group 1, n = 20) with the patients who died or underwent heart transplantation (Group 2, n = 15) did not reveal significant differences in the initial hemodynamic data. However, group 2 patients showed a tendency to higher initial plasma-renin-activity and significantly lower BS 1.3 +/- 0.2 vs. 2.2 +/- 0.3 ms/mm Hg; p < 0.05). CONCLUSION: In patients with heart failure a relation between the renin-angiotensin system and the parasympathetic nervous system is likely as there is a significant negative relationship between BS and plasma-renin-activity. Among patients with a similar degree of heart failure a low vagal tone identifies patients with a poor prognosis.

The background of the MERIT-HF trial.

In the not so distant past, the idea of using beta-blockers as a primary therapy for congestive heart failure to improve symptoms and prognosis seemed paradoxical. The cardiac community reacted with skepticism when, in 1975, the pioneering report of Waagstein et al. appeared in the British Heart Journal. Since then numerous groups have investigated the effects of beta-adrenoceptor antagonists in patients with congestive heart failure. Unfortunately, the results of these trials have sometimes contradicted one another. Exercise tolerance and left ventricular ejection fraction improved in the trials with a duration of treatment of longer than 3 months, but no benefit was observed when beta-blockers were administered for only 1 month. Now, in the year 2000 we have proof for the concept that beta-blockade improves symptoms and prolongs life in heart failure. Three large placebo-controlled clinical trials with more than 9000 patients have shown that carvedilol, bisoprolol and metoprolol significantly reduce morbidity and mortality in heart failure. These agents, therefore, are clearly indicated in the majority of patients with mild to moderate heart failure.

Baroreflex sensitivity and cardiovascular mortality in patients with mild to moderate heart failure.

OBJECTIVE: To assess the influence of both sympathetic (plasma noradrenaline concentrations) and parasympathetic (baroreflex activation) tone on survival in patients with congestive heart failure. DESIGN: Invasive study with determination of parasympathetic activity and follow up for at least 4.5 years. SUBJECTS: 35 patients with sinus rhythm and mild to moderate heart failure (New York Heart Association grades II-III) (mean age 53 (SD 3)). RESULTS: 20 patients whose hearts survived were compared with 15 patients whose hearts did not (12 died and three received transplants). The two groups differed significantly in terms of mean arterial blood pressure (98 (3) v 90 (3) mm Hg), heart rate (82 (2) v 93 (4) beats/min), and mean pulmonary artery pressure (24 (3) v 35 (2) mm Hg) (all P < 0.05), while cardiac index, stroke volume index, and right atrial pressures were not different. The survivors had significantly lower plasma renin activities (3.6 (0.8) v 9.0 (3.6) angiotensin I/ml/h; P < 0.05) and tended to have lower noradrenaline values than non-survivors (170 (23) v 286 (74) pg/ml) at baseline. Baroreflex sensitivity was significantly lower in non- survivors than in survivors (1.3 (0.2) v 2.3 (0.3) ms/mm/Hg); P < 0.02). As the time of cardiac transplantation is dependent on complex logistical factors the three patients who received a transplant were excluded from the analysis of survival time. The risk of death in relation to baroreflex sensitivity at the median sensitivity of 1.48 ms/mm Hg was calculated. Survival was significantly different (P < 0.04) between the resulting two groups; three of the 16 subjects with high baroreflex sensitivity died compared with nine of the 16 with a baroreflex sensitivity < 1.48 ms/mm Hg. When systemic blood pressure, pulmonary artery pressure, stroke volume index, plasma noradrenaline concentrations, and baroreflex sensitivity were entered into a Cox proportional hazards regression, only systolic blood pressure and plasma noradrenaline values predicted survival (P < 0.001). CONCLUSIONS: Low vagal tone is correlated with a poor prognosis in patients with heart failure. Sympathetic tone measured as plasma noradrenaline concentration also contributed to survival. An additional contribution of vagal tone to survival could not be shown when sympathetic tone was considered simultaneously. This may be due to the inverse relation of sympathetic and parasympathetic tone and to the insensitivity of the multiple regression method to identify additional risk factors in small numbers of patients.

Magnetic resonance planimetry of the vena contracta as a new approach to assessment of stenotic heart valves: an in vitro study.

Exact determination of the orifice area in stenotic valve disease is essential to guide therapy. With the standard imaging methods, the orifice area has to be calculated by empirically-derived formulas, which may be susceptible to changes in hemodynamic status, leading to wrong therapeutic decisions. We tested the ability of magnetic resonance imaging (MRI) to quantify the orifice area by planimetry of the proximal vena contracta (PVC) in an idealized, constant-flow model in a 1.0-T tomograph (Siemens Magnetom Expert). There was a close correlation of the PVC area in MRI and the true orifice area (r2 = 0.985), and agreement of the methods as measured by the Bland-Altman test was significant with a low systematic error of -0.02 cm2. We conclude that MRI planimetry of the PVC in stenotic valves in a constant-flow model may be used to reliably measure the orifice area.

Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy.

BACKGROUND: Some studies have suggested that treatment with recombinant human growth hormone (rhGH) increases left-ventricular mass and improves haemodynamic and functional status in patients with heart failure due to dilated cardiomyopathy. We did a double-blind, randomised, placebo-controlled study of rhGH in patients with chronic heart failure due to dilated cardiomyopathy. METHODS: 50 patients (43 men) were randomly allocated treatment with subcutaneous rhGH (2 IU daily) or placebo for a minimum of 12 weeks. The primary endpoints were the effects on left-ventricular mass and systolic wall stress. The secondary endpoints were the effects on left-ventricular size and function. Data were analysed by intention to treat. FINDINGS: Patients in the rhGH group had an increase in left-ventricular mass compared with those in the placebo group (27%, p=0.0001). There was no significant difference in left-ventricular systolic wall stress, mean blood pressure, or systemic vascular resistance between the two groups. New York Heart Association functional class, left-ventricular ejection fraction, and distance on the 6 min walking test were unchanged. The change in serum insulin-like growth factor (IGF)-I concentrations (rhGH 77 ng/mL; placebo -19 ng/mL, GH vs placebo p=0.0001) was significantly related to the change in left-ventricular mass (r=0.55, p=0.0001). One patient in the rhGH group was withdrawn at 6 weeks because of worsening heart failure. INTERPRETATION: There is a significant increase in left-ventricular mass in patients with dilated cardiomyopathy given rhGH but this is not accompanied by an improvement in clinical status. Changes in left-ventricular mass are related to changes in serum IGF-I concentrations. Whether a longer treatment period would provide clinical benefits and decrease mortality is unknown.